Among individuals with human immunodeficiency virus (HIV) infection, effective antiretroviral therapy (ART) has resulted in a marked increase in survival, so that about half of people living with HIV (PLWH) in the US are now 50 years of age or older. Cardiovascular diseases are common among aging PLWH, often at much higher rates than in the general population. This is likely due to a complex interplay of HIV infection and resulting inflammation, ART and its toxicities, viral co-infections, other co-morbid conditions, traditional risk factors, and other behaviors such as substance abuse. Atrial fibrillation (AF) is a common cardiac arrhythmia, strongly associated with aging, that confers substantially elevated risks of stroke, more rapid cognitive decline, dementia, and heart failure in the general population. The pathogenesis of AF involves inflammation, fibrosis, and atrial remodeling. The chronic inflammation associated with HIV infection may contribute to early onset of the arrhythmia in PLWH. Therapeutic advances that reduce chronic inflammation, such as effective ART, may reduce AF. Yet little is known about AF in PLWH. The proposed project will determine the incidence of AF, rigorously assess its risk factors, and determine the risk of AF complications in PLWH. Understanding the contribution of multiple factors to the increased risk of AF is crucial to developing strategies to improve AF prevention, diagnosis, and treatment in PLWH. This application leverages comprehensive clinical data from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a well-established dynamic cohort of over 32,000 PLWH receiving clinical care. Data on AF in uninfected individuals will come from the Multi-Ethnic Study of Atherosclerosis (MESA), in which AF is already ascertained using validated methods in an ongoing fashion. The large, diverse CNICS cohort captures longitudinal clinical data and patient-reported outcomes, facilitating a detailed approach to addressing risk in PLWH. In addition, CNICS infrastructure allows AF outcomes to be identified and carefully validated by review of original medical records, permitting us to identify acute conditions that predispose to AF. The multidisciplinary research team for this project is uniquely poised to address important gaps in understanding the pathophysiology, diagnosis, treatment, and impact of AF in relation to HIV infection by pursuing four aims. Aim 1 is to determine the age, sex-, and race-specific incidence of AF in PLWH. Aim 2 is to identify patient characteristics associated with AF in PLWH, including precipitants such as sepsis, drug intoxication, and intrathoracic disease. Aim 3 is to evaluate an existing AF risk model and to develop and test new risk models for AF prediction in PLWH. Finally, Aim 4 is to examine outcomes in PLWH following clinical recognition of AF. New knowledge gained from these investigations will inform clinical decision-making and will improve understanding of the mechanisms of AF, which will enhance the development of rational and targeted therapeutic approaches to improve outcomes.